This invention relates to a process for preparing an optically active oxazolidinone derivative which is useful as a starting material for pharmaceuticals or optically active amino-alcohols.
Optically active oxazolidinone derivatives are known as important intermediates for xcex2-blockers (see S. Hamaguchi et al., Agric. Biol. Chem., vol. 48, pp. 2055 and 2331 (1984) and idem, ibid., vol. 49, pp. 1509, 1661 and 1669 (1985)), antidepressants (e.g., JP-A-3-218367), and antibacterials (see. Drugs Fut., vol. 21, p. 116 (1996) and EP 0789025A1), and an economical process of preparing them has been demanded.
Conventional processes of preparing an optically active oxazolidinone derivative include (1) a process comprising cyclizing an amino-alcohol obtained from an optically active epoxide with a dialkyl carbonate (see J. Med. Chem., vol. 32, p. 1673 (1989)), (2) a process comprising ring opening of an optically active epoxide with an isocyanate or an acylazide (see J. Med. Chem., vol. 32, p. 1673 (1989)), and (3) a method of synthesis starting with D-mannitol, L-ascorbic acid or (R)- or (S)-malic acid (see Tetrahedron:Asymmetry, vol. 6, p. 1181 (1995)).
Processes for synthesizing a racemic oxazolidinone derivative include (4) a process comprising cyclizing a xcex2-hydroxycarboxylic acid with diphenylphosphorylazide (see Kor. J. Med. Chem., vol. 4, p. 52 (1994) and Bull. Korean Chem. Soc., vol. 15, p. 525 (1996)), and (5) a process comprising Curtius rearrangement of xcex2-hydroxypropionohydrazide (see Heterocycles, vol. 6, p. 1604 (1977), Tetrahedron:Asymmetry, vol. 8, p. 477 (1997), and Liebigs Ann. Chem., p. 150 (1979)).
However, these processes (1) to (5) have their several disadvantages as follows.
Process (1) (J. Med. Chem., vol. 32, p. 1673 (1989)) comprises optically resolving an amino-alcohol obtained from aniline and an epoxide with optically active mandelic acid, allowing diethyl carbonate to act on the resulting optically active amino-alcohol to obtain an oxazolidinone derivative as shown below. This process has poor economical efficiency because the undesired one of the optically active amino-alcohols obtained by the optical resolution with mandelic acid is to be discarded. 
Process (2) (J. Med. Chem., vol. 32, p. 1673 (1989)) comprises allowing an optically active epoxide obtained by enzymatic optical resolution to react with an isocyanate to give an optically active oxazolidinone derivative as illustrated below. The optically active epoxide used is prepared by biological resolution of an optically active C3 chlorohydrin type compound, which requires a large quantity of a solvent and involves by-production of an equal amount of an unnecessary stereoisomer. Therefore, the production efficiency is low. 
Process (3) according to Tetrahedron:Asymmetry, vol. 6, p. 1181 (1995) involves many steps, no matter which of D-mannitol, L-ascorbic acid, and (R)- or (S)-malic acid is used as a starting material. For example, the synthesis starting with D-mannitol proceeds as follows. 
Besides requiring may steps, the process starting from D-(S)-malic acid uses diphenylphosphorylazide that is expensive.
Process (4) according to Kor. J. Med. Chem., vol. 4, p. 52 (1994) comprises allowing diphenylphosphorylazide to react on xcex2-hydroxycarboxylic acid to carry out Curtius rearrangement to obtain a racemic oxazolidinone derivative as illustrated below. As stated above, diphenylphosphorylazide is expensive. Moreover, the reaction is conducted at 80xc2x0 C. at which there is a danger of explosion, which is unsuited to industrial production. 
The process (4) according to Bull. Korean Chem. Soc., vol. 15, p. 525 (1996) also requires expensive diphenylphosphorylazide, and the reaction is conducted at 80xc2x0 C. at which there is a danger of explosion.
Process (5) (Tetrahedron:Asymmetry, vol. 8, p. 477 (1997)) comprises converting a xcex2-hydroxy ester obtained by optical resolution with lipase into a hydrazide, which is subjected to Curtius rearrangement to give an optically active oxazolidinone derivative as illustrated below. According to this technique, an acylazide is produced at 5xc2x0 C. or below, and the reaction system is warmed to room temperature, at which it is stirred overnight to produce a desired compound. Since the Curtius rearrangement is performed at room temperature, it needs a long time. The acylazide, being left to stand at room temperature for a long time, involves a danger of explosion, which is not suited to industrial production. 
Also, in the process disclosed in Heterocycles, vol. 6, p. 1604 (1977) and Liebigs Ann. Chem., p. 150 (1979), since a low temperature reaction system having produced an intermediate acylazide is heated to carry out the rearrangement reaction, there will be a danger of explosion where the reaction is performed on an industrial scale.
An object of the invention is to provide a novel process for obtaining an optically active oxazolidinone derivative having high optical purity in high yield without being accompanied with the above-mentioned various problems of conventional techniques.
In the light of the above circumstances, the present inventors have conducted extensive investigations, seeking for an effective and economical process for preparing an optically active oxazolidinone derivative. As a result, they have found a novel process which can achieve high optical purity and high yield with high production efficiency and no process complexity.
The invention relates to:
(1) A process for preparing an optically active oxazolidinone derivative represented by formula (I): 
wherein R1 represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group which may have a substituent or substituents on the benzene ring thereof, an acylaminomethyl group having 3 to 10 carbon atoms, or an alkyloxycarbonylaminomethyl group having 3 to 6 carbon atoms; R2 and R3, which may be the same or different, each represent a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group; and * indicates an asymmetric carbon atom, comprising allowing hydrazine to react with an optically active acid ester having a hydroxyl group at the 3-position which is represented by formula (II): 
wherein R1, R2, R3, and * are as defined above; and R4 represents a lower alkyl group having 1 to 4 carbon atoms, to give an optically active hydrazide having a hydroxyl group at the 3-position which is represented by formula (III): 
wherein R1, R2, R3, and * are as defined above, and subjecting the optically active hydrazide to Curtius rearrangement.
(2) A process for preparing an optically active oxazolidinone derivative as set forth above, wherein the optically active hydrazide represented by formula (III) is recrystallized to increase its purity.
(3) A process for preparing an optically active oxazolidinone derivative as set forth above, wherein the optically active acid ester having a hydroxyl group at the 3-position is a compound represented by formula (II) wherein R1 represents a methyl group, phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group, an acetylaminomethyl group, a hexanoylaminomethyl group, or a t-butoxycarbonylaminomethyl group; R2 and R3 both represent a hydrogen atom, or one of R2 and R3 represents a hydrogen atom with the other representing an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group; and R4 represents a lower alkyl group having 1 to 4 carbon atoms.
Further, in the above-described compounds represented by formula (I) or (III), those wherein R1 is an acylaminomethyl group having 3 to 10 carbon atoms or an alkyloxycarbonylaminomethyl group having 3 to 6 carbon atoms and R2 and R3 each represent a hydrogen atom should be novel compounds which haven""t so far been known or reported. The present inventors have found that these compounds are useful as intermediates for producing pharmaceuticals or starting materials for producing optically active amino-alcohols.
In particular, the following compound represented by formula (Ixe2x80x2) is useful as an intermediate for producing linezolid (a product a Pharmacia and Upjohn, Inc.), which is useful as an antibiotic compound. 
A typical production example of the above novel compounds is as follows. First, an optically active azide compound of xcex2-hydroxylate is obtained by allowing an asymmetrically hydrogenated product of xcex2-hydroxylate to react with sodium azide (see JP-A-8-119935). The azide compound is acylated by an ordinary method, and then is subjected to reductive rearrangement reaction to obtain an acylamide (a) (see J. Org. Chem., 58, 1287 (1993)). Alternatively, the above obtained azide compound is subjected to reductive rearrangement reaction in the co-presence of di-tert-butyldicarbonate ((Boc)2O) to obtain an optically active xcex2-hydroxylate where an amino group is protected (b) (see Tetrahedron Lett., 30, 837 (1989)). The above obtained acylamide (a) or hydroxylate (b) is allowed to act on a hydrazine, and then the resulting compound is subjected to Curtius rearrangement to obtain a novel optically active oxazolidinone compound.
The optically active ester derivative having a hydroxyl group at the 3-position represented by formula (II), which can be used as a starting compound, is prepared by asymmetric hydrogenation of a xcex2-keto ester represented by formula (IV): 
wherein R1, R2, R3, and R4 are as defined above.
The xcex2-keto ester of formula (IV) wherein R1 is a lower alkyl group having 1 to 4 carbon atoms or a phenyl group is synthesized from an easily available 3-ketobutyric ester (acetoacetic ester) in a known manner, for example by the reaction between an acetoacetic ester and an acid halide as taught in JP-A-10-53561. The xcex2-keto ester of formula (IV) wherein R1 is a methoxymethyl group or a benzyloxymethyl group (i.e., a 4-alkoxy-3-oxybutyric ester) is synthesized from an easily available 4-halogeno-3-oxopropionic ester in a known manner, for example the process disclosed in R. M. Kellogg et al., J. Chem. Soc., Chem. commun., p. 932 91997) or D. Seebach et al., Synthesis, p. 37 (1986). The xcex2-keto ester of formula (IV) wherein R1 is a group carrying an aminomethyl moiety having a protective group on its nitrogen atom (i.e., a benzyloxycarbonylaminomethyl group) is synthesized from, for example, easily available benzyloxycarbonylglycine in a known manner, for example, the process disclosed in Natsugari et al., Synthesis, p. 403 (1992).
Where R1 in the xcex2-keto ester of formula (IV) is a benzyloxycarbonylaminomethyl group, an acylaminomethyl group, or an alkyloxycarbonylaminomethyl group, the benzyl moiety of the amino protective group may have one or more substituents. Examples of the substituents include a lower alkyl group having 1 to 4 carbon atoms (preferably methyl or t-butyl), a lower alkoxy group having 1 to 4 carbon atoms (preferably methoxy), a halogen atom (e.g., chlorine). Examples of the substituted benzyl group are p-methoxybenzyl, 2,4-dimethoxybenzyl, p-methylbenzyl, 3,5-dimethylbenzyl, p-chlorobenzyl, and p-t-butylbenzyl.
Examples of the acyl group are acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, and decanoyl.
Examples of the alkyloxycarbonyl group are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and t-butoxycarbonyl.
The xcex2-keto ester of formula (IV) which has a substituent(s) at the 2-position, for example where R2 and/or R3 is an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group can be synthesized according to the process described in JP-A-2-231471.
Asymmetric hydrogenation of the xcex2-keto ester of formula (IV) can be conveniently carried out in accordance with the method of JP-A-2-289537. That is, the reaction is conducted in an alcohol solvent in the presence of a catalytic amount of a ruthenium-optically active phosphine complex under a hydrogen pressure of 500 to 10000 Kpa at 10 to 100xc2x0 C. for 5 to 20 hours.
The ruthenium-optically active phosphine complex which is preferably used includes the complex described in JP-61-63690 which is represented by formula (V):
(Ru)a(H)b(Cl)c(R5-BINAP)2(T)dxe2x80x83xe2x80x83(V)
wherein R5-BINAP represents a tertiary phosphine represented by formula (VI): 
R5 represents a hydrogen atom, a methyl group, a t-butyl group or a methoxy group; T represents a tertiary amine; b represents 0 or 1; when b is 0, a is 2, c is 4, and d is 1; and when b is 1, a is 1, c is 1, and d is 0, and the complex described in JP-A-62-265293 which is represented by formula (VII):
(Ru)(R5-BINAP)(O2CR6)2xe2x80x83xe2x80x83(VII)
wherein R5-BINAP is as defined above; and R6 represents a lower alkyl group having 1 to 4 carbon atoms or a trifluoromethyl group.
The tertiary phosphine (R5-BINAP) of formula (VI) specifically includes 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (hereinafter referred to as BINAP), 2,2xe2x80x2-bis[di(p-tolyl) phosphino]-1,1xe2x80x2-binaphthyl (hereinafter referred to as Tol-BINAP), 2,2xe2x80x2-bis[di(p-t-butylphenyl) phosphino]-1,1xe2x80x2-binaphthyl (hereinafter referred to as t-Bu-BINAP), and 2,2xe2x80x2-bis[di(p-methoxyphenyl) phosphino]-1,1xe2x80x2-binaphthyl (hereinafter referred to as Methoxy-BINAP).
These tertiary phosphines of formula (VI) each take a (+)-form or (xe2x88x92)-form, which is selected in agreement with the absolute configuration of a desired optically active compound of formula (II). That is, a (+)-form is chosen for obtaining a (3R)-compound; and a (xe2x88x92)-form for a (3S)-compound.
The tertiary amine (T) in formula (V) includes triethylamine, tributylamine, ethylisopropylamine, 1,8-bis(dimethylamino) naphthalene, dimethylaniline, pyridine, and N-methylpiperidine, with triethylamine being preferred.
The following complexes 1 to 8 are examples of the complex represented by formula (V) and complexes 9 through 16 are examples of the complex represented by formula (VII), in which representation of the absolute configuration of the tertiary phosphine is omitted. xe2x80x9cEtxe2x80x9d stands for an ethyl group; xe2x80x9cTolxe2x80x9d, a tolyl group; and xe2x80x9ct-Buxe2x80x9d a t-butyl group.
Complex 1: Ru2Cl4(BINAP)2NEt3 
Complex 2: Ru2Cl4(tol-BINAP)2NEt3 
Complex 3: Ru2Cl4(t-Bu-BINAP)2NEt3 
Complex 4: Ru2Cl4(Methoxy-BINAP)2NEt3 
Complex 5: RuHCl(BINAP)2 
Complex 6: RuHCl(Tol-BINAP)2 
Complex 7: RuHCl(T-Bu-BINAP)2 
Complex 8: RuHCl(Methoxy-BINAP)2 
Complex 9: Ru(BINAP) (O2CCH3)2 
Complex 10: Ru(Tol-BINAP) (O2CCH3)2 
Complex 11: Ru(t-Bu-BINAP) (O2CCH3)2 
Complex 12: Ru(Methoxy-BINAP) (O2CCH3)2 
Complex 13: Ru(BINAP) (O2CCF3)2 
Complex 14: Ru(Tol-BINAP) (O2CCF3)2 
Complex 15: Ru(T-Bu-BINAP) (O2CCF3)2 
Complex 16: Ru(Methoxy-BINAP) (O2CCF3)2 
The ruthenium-optically active phosphine complex is used in an amount of {fraction (1/100)} to {fraction (1/10000)} mol, preferably {fraction (1/500)} to {fraction (1/4000)} mol, per mole of the xcex2-keto ester, the substrate of asymmetric hydrogenation. The asymmetric hydrogenation is conveniently carried out in an alcohol solvent, particularly methyl alcohol, ethyl alcohol or isoporopyl alcohol. Ethyl alcohol is the most preferred solvent. The amount of the solvent to be used is usually 1 to 5 times (by volume/weight) the substrate.
The optically active hydrazide represented by formula (III) is synthesized by allowing hydrazine to react on the optically active acid ester represented by formula (II), which is prepared by the above-described asymmetric hydrogenation, in an alcohol solvent. The reaction usually proceeds at 0 to 100xc2x0 C., preferably 30 to 70xc2x0 C.
Preferred alcohol solvents include methyl alcohol, ethyl alcohol, and isopropyl alcohol. Hydrazine is used in an amount of 1 to 5 mol, preferably 1.1 to 1.5 mol, per mole of the compound of formula (II). After completion of the reaction, the resultant crude optically active hydrazide is purified by recrystallization from methanol containing isopropyl alcohol and filtered to give an optically active hydrazide having a hydroxyl group at the 3-position as represented by formula (III) having optical purity in a high yield.
In the final stage of the process of the invention, Curtius rearrangement is effected on the optically active hydrazide of formula (III) to give an optically active oxazolidinone derivative of formula (I).
Unlike the process taught by the literature, P.A.S. Smith, Organic Reactions, vol. 11, p. 337 (1946), the Curtius rearrangement applied to the invention is performed by allowing sodium nitrite to react on the optically active hydrazide having a hydroxyl group at the 3-position as represented by formula (III) in the presence of an acid to once produce an intermediate acyl azide, and allowing the reaction mixture as containing the acyl azide to stand or adding the reaction mixture dropwise to a heated solvent, thereby to yield the desired optically active oxazolidinone derivative of formula (I) in a safe manner.
The amount of sodium sulfite to be used ranges 1 to 2 mols, preferably 1.1 to 1.3 mols, per mole of the hydrazide (III). The acid which can be used in the Curtius rearrangement as intended in the invention includes hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sulfonic acid, methanesulfonic acid, and p-toluenesulfonic acid. Preferred of them are hydrochloric acid, sulfuric acid, and acetic acid. Solvents which can be used in the reaction include halogenated hydrocarbons, such as methylene chloride and chloroform; ketones, such as acetone; esters, such as ethyl acetate and butyl acetate; ethers, such as diethyl ether and diisopropyl ether; alcohols, such as methanol, ethanol, and butanol; hydrocarbons, such as hexane, heptane, toluene, and benzene; water; and mixtures thereof. Water or a mixed solvent of water and an ether is particularly preferred. The reaction temperature ranges from 20 to 100xc2x0 C., preferably from 30 to 50xc2x0 C. According to the process of the invention, the stereoisomerism of the optically active hydrazide of formula (III) can be retained throughout the Curtius rearrangement to give the desired optically active oxazolidinone derivative of formula (I) having the desired stereoisomerism.
The present invention provides a novel process of producing an optically active oxazolidinone derivative at high production efficiency with no process complexity. The invention also provides a novel process of producing an optically active oxazolidinone derivative having high optical purity in high yield.
The invention will now be illustrated in greater detail with reference to Reference Examples and Examples, but it should be understood that the invention is not limited thereto. Measurement of physical properties in Examples was made with the following instruments unless otherwise specified.
1) Nuclear magnetic resonance (NMR) spectrum
A. 2H-NMR: Gemini 200 (200 MHz), manufactured by Varian, Inc. DRX500 (500 MHz), manufactured by Bruker Japan, Co., Ltd.
Internal standard: tetramethylsilane
B. 13C-NMR: Gemini 200 (50 MHz), manufactured by Varian, Inc. DRX500 (126 MHz), manufactured by Bruker Japan, Co., Ltd.
Internal standard: tetramethylsilane
2) Melting point
MP-S3, available from Yanagimono Shoji K. K.
3) High-performance liquid chromatography (HPLC)
Liquid Chromatograph L-600, manufactured by Hitachi, Ltc.
4) Gas chromatography (GC)
5890-II, manufactured by Hewlett Packard
The product was led to its MTPA ester or MTPA amide for determination of the optical purity, wherein MTPA stands for (R)- or (S)-xcex1-methoxy-xcex1-(trifluoromethyl)phenylacetic acid.